The delayed phase of restitution of blood volume after hemorrhage appears to depend upon multiple hormonal changes and may be important for ultimate stabilization of the cardiovascular system. The nature of the interrelations among hormonal, metabolic and cardiovascular changes will be explored in experiments in dogs and monkeys. Hormonal changes necessary for extracellular hyperosmolality, protein and fluid restoration will be defined. The nature of the metabolic components responsible for changes in osmolality will be examined and related to hormonal changes. The effects of osmotic changes on fluid shifts from cells to interstitium will be defined, and the effect of these changes on interstitial pressure and on return of protein and fluid to the circulation will be studied. The dependence of cardiovascular stabilization on the second phase of restitution of blood volume will be studied during the period from 2 to 24 hours after hemorrhage or injury. Additional experiments will examine the role of factors such as pain and injury in modification of the hormonal and metabolic response to volume loss, mechanisms controlling secretion of hormonal factors other than ACTH involved in volume changes and the sensitivity of hormonal and metabolic changes to volume expansion. These studies may serve to define the degree to which the hormonal and metabolic responses to trauma can be viewed as a delayed cardiovascular reflex, and to define the importance of this reflex.